Injured or damaged parts of the hard and/or soft tissue of the human body are restored or mechanically reinforced the best by using autologous hard and/or soft tissue. This is not always possible for various reasons, which is why in many cases synthetic material is used as a temporary (biodegradable or post-operatively removable) or permanent replacement material.
Implants which are anchored in the hard and/or soft tissue serve the temporary or permanent replacement or the support of parts of the human body which have been impaired by accident, abrasion, deficiency or sickness or otherwise degenerated. Normally, an implant is referred to as an artificial, chemically stable material which is introduced into the body as a plastic replacement or for mechanical reinforcement (see e.g. Roche Lexikon Medizin, Urban & Fischer (Eds.); 5th edn. 2003). The support- and replacement function in the body is taken over on the basis of the mechanical characteristics and the implant design. Therefore, for instance the hip- and knee joint prostheses, spinal implants and vessel prostheses have been successfully used clinically for many years. For the anchoring of the implant and the implant tolerance at the interface implant surface/neighboring tissue, the implant surface has a great significance. By a change of the implant surface, the recovery process can be accelerated.
Various methods are used for surface treatment and surface structuring, as e.g. Titanium in Medicine, Material Science, Surface Science, Engineering, Biological Responses and Medical Applications Series: Engineering Materials, (Brunette, D. M.; Tengvall, P.; Textor, M.; Thomsen, P. (Eds.)); and the references cited therein.
The increase of roughness is for example well established (for many, see Titanium in Medicine, Material Science, Surface Science, Engineering, Biological Responses and Medical Applications Series: Engineering Materials, (Brunette, D. M.; Tenvall, P.; Textor, M.; Thomsen, P. (Eds.)).
Furthermore, papers exist which describe the chemical modification of implant surfaces in order to achieve a better connection of the bone to the implant surface (Xue W., Liu X, Zheng X, Ding C, Biomaterials. 2005 June; 26 (16): 3029-37).
More recent approaches are pharmaceutical modifications of the surface in order to accelerate the osseointegration of the implants and/or to promote or to stimulate the regeneration of the surrounding hard and/or soft tissue, e.g. with growth factors (Raschke M J, Schmidmaier G. Unfallchirurg. 2004 August; 107(8): 653-63).
By contrast, layers loaded with active substances can serve to prevent unwished reactions to implants, for example vessel prostheses (Hausleiter J, et al., Eur. Heart J. 2005 August; 26(15): 1475-81. Epub 2005 Jun. 23).
Other medication groups interesting for pharmaceutical surface modification are pharmaceuticals which were developed for the systemic treatment of osteoporosis, as for example calcitonin, strontiumranelate and various bisphosphonates.
Bisphosphonates can be interpreted as structural analogs of pyrophosphate, in which the P-O-P-group is replaced by an enzymatically stable P-C-P-group. By substitution of the hydrogen atoms at the C-atom of the P-C-P-group, bisphosphonates with various structural elements and characteristics are available. Known bisphosphonates which have been approved for clinical use are e.g. pamidronic acid, alendronic acid, ibandronic acid, clodronic acid or etidronic acid. In medicine, bisphosphonates have been established in the treatment of metabolic bone diseases, especially tumor-associated hypercalcemias, osteolytic bone metastases and postmenopausal and glucocortico-induced osteoporoses. Furthermore, tests show that bisphosphonates can be used for the prevention or for the treatment of vascular restenosis (WO 02/003677).
Depending on their structure, some of the known bisphosphonates clearly differ among each other with respect to their therapeutic efficacy. Especially those bisphosphonates which have an amino-function between the two phosphorus-atoms in the structural unit have a high therapeutic efficacy. Below, these compounds are referred to as amino-bisphosphonates.
The pharmacological action of the bisphosphonates is based on a high affinity to calcium phosphate structures of the bone surface, wherein subsequently bone-degrading cells (osteoclasts) are inhibited, which leads to a decrease of the bone resorption and simultaneously to a reactivation of bone-developing cells (osteoblasts). Due to the special pharmacokinetics of the bisphosphonates, a local therapy is preferred compared to the systemic administration.
Based on this knowledge, in the past years, numerous tests were conducted in which the immobilisation of selected bisphosphonates on hard tissue implants and their impact on the ingrowth-behavior of the corresponding implant were tested.
Thus, e.g. in U.S. Pat. No. 5,733,564 the coating of materials (endoprostheses, screws, pins, etc.) with aqueous bisphosphonate-solutions were described with the aim to accelerate the bone-regeneration around the implant. However, the poor adhesion of the bisphosphonates on metallic surfaces and their solubility in water constitute a disadvantage of this approach.
Yoshinari et al. (Biomaterials 23 (2002), 2879-2885) showed by means of in vivo studies that calciumphosphate-coated implants of pure titanium, which had been impregnated with an aqueous pamidronate-solution, showed an improved osteogenesis at the implant surface compared to implants which had not been impregnated with pamidronate. Due to the high affinity of the bisphosphonates to calcium ion-containing substrates, calciumphosphate surfaces constitute a possible substrate for the immobilisation of bisphosphonates, as on these surfaces the bioavailability of the bisphosphonates and thus their therapeutical efficacy by their interaction with calcium ions is present at a higher rate than on surfaces essentially free of calcium ions.
WO-A-02/04038 describes a further variant of the immobilisation of bisphosphonates in hydroxyapatite-containing coatings of bone implants. Because metallic implants play a dominating role in the hard tissue area and on the other hand a calcium phosphate coating of metallic surfaces entails increased production expenses, in the past, numerous attempts were made to modify metallic implant materials such that an effective bisphosphonate-immobilisation is enabled thereon.
Therefore, studies became known in which calcium ions are brought into the surface of titanium implants by electron beam-implantation (JP 2000070288, H. Kajiwara et al. Biomaterials 26 (2005), 581-587), in order to achieve an improved adhesion of bisphosphonates. However, this method has the disadvantage of high apparatus-related expenses.
Further studies concern the electrolytic separation of calcium-etidronate on pure titanium (K. Duan et al., J. Biomed. Mater. Res.: Appl. Biomater. 72B (2005), 43-51), wherein on the one hand thin films of bisphosphonate were able to be separated, however, they showed inhomogeneities and signs of shrinking during the drying process.
In WO-A-2005/018699, bisphosphonate-coated metallic implants are described, which were produced in a way that first, a protein layer, for example of fibrinogen is immobilized on the metallic surface. Subsequently, one or more bisphosphonates are covalently bound to this protein layer via reactive functional groups. A significant disadvantage of this method lies in the use of toxic reagents during the immobilisation or cross-linking, respectively, of the protein layer and the covalent coupling of the bisphosphonate.